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Stressor-Selective Role of the Ventral Subiculum in Regulation of Neuroendocrine Stress Responses

Departments of Psychiatry (N.K.M., C.M.D., J.P.H.) and Cell Biology, Neurobiology, and Anatomy (J.P.H.), University of Cincinnati Medical School, Cincinnati, Ohio 45237

Address all correspondence and requests for reprints to: James P. Herman, Ph.D., Department of Psychiatry, University of Cincinnati, 2170 East Galbraith Road, Cincinnati, Ohio 45237-0506. E-mail: james.herman{at}uc.edu.

	Abstract

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The ventral subiculum (vSUB) confers inhibitory effects of the hippocampus on hypothalamo-pituitary-adrenocortical (HPA) axis responses to novelty and restraint. The current study was designed to evaluate the role of the vSUB in regulating HPA axis responses to stressors of diverse modalities. Male Sprague Dawley rats received bilateral ibotenic acid or saline injections into the region of the vSUB. Corticosterone secretion was assessed after exposure to hypoxia and elevated plus maze, with the two stress exposures occurring 5 d apart. Peak corticosterone responses to hypoxia were reduced in vSUB-lesion animals, indicating an attenuation of HPA axis responsiveness. A subsequent study revealed that hyporesponsivity to hypoxia was evident in chamber-naive as well as chamber-adapted animals, verifying that this effect was independent of previous experience in the testing environment. In contrast, the effects of vSUB lesions on corticosterone responses to the elevated plus maze exposure were substantially more circumspect, being limited to a slight increase in secretion at the 2-h poststress time point. The limited vSUB lesion-induced increase in the plasma corticosterone response to elevated plus maze exposure occurred despite an increased open-arm time in the maze, suggesting that lesions reduced anxiety-like behavior. In combination with previous studies, these data suggest that the vSUB has excitatory as well as inhibitory input into HPA axis responsivity, depending on the nature of the stressful stimulus, and suggest that behavioral and neuroendocrine responses to stressful or anxiogenic stimuli may be dissociable.

	Introduction

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GLUCOCORTICOIDS REGULATE NUMEROUS homeostatic and neural processes relevant to energy metabolism, immunity, mood and cognition (1, 2, 3). Due to the widespread peripheral and central effects of glucocorticoid hormones, plasma levels of the adrenocorticosteroids are under tight control by the hypothalamic-pituitary-adrenal (HPA) axis. Several hypothalamic factors, principally CRH (4, 5), stimulate ACTH secretion from the anterior pituitary, which then drives synthesis and release of corticosteroids by the adrenal cortex. The HPA cascade is initiated by neurons located in the medial parvocellular paraventricular nucleus (PVN) of the hypothalamus, which act as motoneurons of the stress response, integrating excitatory and inhibitory impulses into a neuroendocrine signal (4, 5). The magnitude and duration of stress-stimulated glucocorticoid secretion is limited by humoral and neuronal feedback (6), returning the system to basal secretory tone. Adequate balance of excitation and inhibition of the HPA axis is critical, as hypo- or hypersecretion of glucocorticoids are associated with neuropsychiatric and metabolic disease states (7, 8).

Regulation of the HPA system is accomplished by a diverse neurocircuitry, which prominently includes limbic sites such as the hippocampus. Lesion studies indicate that the hippocampus has an inhibitory influence on HPA responses to novelty (9, 10), restraint (11, 12), or auditory stimulation (13). Conversely, stimulation of the hippocampus can actively inhibit HPA activation (14, 15). Inhibitory effects are likely to be mediated by principal output neurons in the ventral subiculum (vSUB), as lesion of this relatively circumscribed region of parahippocampal cortex recapitulates enhanced HPA responsiveness seen by total hippocampal lesion or fimbria-fornix section (12). However, hippocampal/fimbria-fornix damage does not appear to potentiate HPA responses to all stressors; for example, lesions do not affect corticosterone (CORT) secretion after ether inhalation (10, 16, 17) or hypoxia (16, 18). The latter studies suggest that the hippocampus is not a universal component of central stress-integrative circuitry and may thus be related to stimulus modality.

Importantly, hippocampal inhibition of the HPA axis is typically exerted at the level of response duration, consistent with a putative role for this region in glucocorticoid negative feedback integration (11). Indeed, the hippocampus expresses abundant glucocorticoid and mineralocorticoid receptors (19, 20), making it a prime candidate for regulation of feedback. Consistent with this hypothesis, hippocampal lesions can decrease negative feedback sensitivity to dexamethasone (17); however, lesions do not inhibit CORT feedback inhibition of ACTH responses to hypoxia or restraint (10, 18).

Previous attempts to synthesize this divergent data have fueled the hypothesis that hippocampal involvement in stress termination and/or feedback is dependent on the extent to which an evocative stimulus engages the hippocampus (21). To test this hypothesis, the current study uses a within-subjects design to test the involvement of the vSUB in responses to spatial (novel elevated plus maze) and nonspatial (hypoxia) stimuli.

	Materials and Methods

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Male Sprague Dawley rats (275–350 g) (Harlan, Indianapolis, IN) were individually housed in a constant temperature and humidity vivarium on a 12:12-h light:dark cycle, with food and water ad libitum. One week after arrival, rats were anesthetized with ketamine (87 mg/kg)/xylazine (13 mg/kg) ip and received either bilateral stereotaxic injections of ibotenic acid (3.5 µg) (n = 17) or saline (n = 10) into the vSUB (–6.2 mm posterior to bregma, ±5.1 mm lateral, and –8.2 mm ventral to the surface of the brain) over a 30-min period, using the coordinate system of Paxinos and Watson (22). All procedures were conducted in accordance with National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and were approved by the University of Cincinnati Institutional Animal Care and Use Committee.

Stress protocol
Operated animals were allowed to recover from surgery for 10 d, at which point stress testing was initiated (Fig. 1). Animals were habituated to the hypoxia chamber for 3 d before testing (30 min/d). On the subsequent day, animals were subjected to hypoxia for 30 min, accomplished by saturating the chamber with a 9% oxygen, 91% nitrogen mixture. Blood was sampled by tail-nick 30, 60, and 120 min after initiation of hypoxia. All animals were replaced in their home cages after 30 min; thus, at the 60- and 120-min time points rats were removed from their home cages and lightly restrained, and blood was sampled within 3 min of retrieval. Five days later, rats were exposed to an elevated plus maze (EPM) for 5 min. Sessions were videotaped for behavioral analysis. Blood was sampled by tail-nick by light restraint 30, 60, and 120 min after EPM placement, as noted above. Fourteen days after EPM stress testing, blood samples were taken by tail-nick in the morning to determine basal ACTH and CORT levels. Rats were lightly restrained during this process, and blood was sampled within 60 sec of removal from their home cages.

View larger version (8K): [in this window] [in a new window]   FIG. 1. Diagram of stress protocol.

Plasma hormone assays
Plasma samples were processed for RIA for CORT and ACTH without extraction. Plasma CORT was determined using a double-antibody RIA kit from ICN (Costa Mesa, CA) using [¹²⁵I]CORT as tracer. The detection limit for the CORT assay was 0.25 ng/ml. Plasma ACTH was determined using a double-antibody RIA kit from Disoran (Stillwater, MN), using [¹²⁵I]ACTH as tracer. The detection limit for the ACTH assay was 10 pg/ml.

Lesion analysis
At the conclusion of the experiment, rats were killed by rapid decapitation and brains removed rapidly and frozen in isopentane at –50 C on dry ice for histological analysis. Adrenal and thymus glands were collected, cleaned, and weighed. Detection and analysis of the extent of the ibotenic acid lesions and saline injection sites were performed by histological analysis of adjacent brain sections stained for Nissl substance with Cresyl violet. The absence of pyramidal neurons in the vSUB-lesion area was the main criterion used to consider a lesion complete (Fig. 2, B and C).

View larger version (72K): [in this window] [in a new window]   FIG. 2. Illustrations of vSUB Lesions. A, Diagrams of largest (light circle) and smallest (dark circles) bilateral ibotenic acid lesions of the vSUB. In all cases, the lateral component of the vSUB was compromised by ibotenic acid injection. B, Cresyl violet-stained section of the corresponding region of a saline-treated rat. Note the presence of intact cellular profiles throughout hippocampal CA1 and subicular pyramidal cell zones. C, Cresyl violet-stained section from a rat receiving bilateral ibotenic acid injections into the vSUB. Note the lack of pyramidal cell profiles in the area delineated by the arrows.

	Results

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Parameters of HPA function were examined after selective destruction of vSUB neurons using the excitatory amino acid neurotoxin ibotenic acid. Injections of neurotoxin in the vSUB caused significant damage to the vast majority of the vSUB; some ventral regions of CA1 and limited portions of dentate gyrus were also compromised (Fig. 2A). Lesions were centered at the middle of the rostrocaudal extent of the vSUB and typically destroyed the vast majority of the structure. However, in all cases there was some degree of sparing of cells located at the rostral and/or caudal extremes of the vSUB. In no case did animals included in the vSUB groups show significant damage to amygdaloid nuclei.

Effects of vSUB lesions on basal HPA activation are summarized in Table 1. As shown previously, baseline ACTH and CORT plasma levels were not affected by vSUB lesions. There was no adrenal hypertrophy (however, note F_1,25 = 3.159; P = 0.09) or thymic atrophy observed in lesioned animals compared with saline controls. Body weight was not affected by lesion (data not shown).

View larger version (16K): [in this window] [in a new window]   FIG. 3. Effects of vSUB lesion on CORT responses to hypoxia and EPM exposure. Values represent sequential samplings from the same subjects by tail-nick, taken 30, 60, and 120 min after stress initiation. A, Hypoxia; exposure to hypoxia diminished CORT responses to stress in vSUB-lesion rats with respect to sham-lesion animals at the 30-min time point. B, EPM; repeated-measures ANOVA demonstrated a significant lesion by time interaction. The effect was carried by elevation of plasma CORT at the 120-min poststress time point. *, Significant difference from the sham-lesion group at the corresponding time point (P < 0.05).

Behavioral reactivity of vSUB-lesion and sham-lesion rats was analyzed by assessment of open arm time, closed arm time, grooming, and fecal boli production across the 5 min of EPM apparatus. Animals with vSUB lesions exhibited increased time in open arm (P < 0.05, Mann-Whitney U test), decreased time in closed arm (P < 0.05, Mann-Whitney U test) (Fig. 4), and decreased fecal boli production (saline 1.50 ± 0.582 vs. ibotenic acid 0.18 ± 0.128; P < 0.05, Mann-Whitney U test) in the EPM. Grooming, rearing, and locomotion were not affected by the lesion. The results are consistent with lesion-induced decreases in anxiety-like behavior in the EPM.

View larger version (18K): [in this window] [in a new window]   FIG. 4. Effects of vSUB lesion on behavioral responses in the EPM. vSUB lesions increased percent time spent in open arms of the EPM (P < 0.05, Mann-Whitney U test). There was no effect of vSUB lesions on incidence of grooming, rearing, or total locomotion.

View larger version (24K): [in this window] [in a new window]   FIG. 5. Effects of vSUB lesions on CORT responses to hypoxia in chamber-adapted and chamber-naive rats. A, Values represent sequential samplings from the same subjects by tail-nick, taken 30, 60, and 120 min after stress initiation. Lesions of the vSUB decreased CORT responses to hypoxia in both adapted and naive groups. B, Bars represent total CORT secretion across the poststress sampling period, calculated by the area under the curve. vSUB lesions significantly decreased integrated CORT secretion after hypoxia in both chamber-adapted and chamber-naive groups.

	Discussion

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Lesion-induced attenuation of CORT secretion after hypoxia is surprising in light of previous work from our group and others demonstrating that vSUB or lateral-fimbria fornix lesions have no effect on systemic stressors, including ether (10, 16, 17) and hypoxia (10, 18). In general, systemic stressors are complex stimuli that have components of both somatic/visceral sensation and homeostatic signaling. Although both ether and hypoxia compromise respiratory capacity to some degree, marked differences in the central neuronal activation patterns elicited by these suggest that sensorial aspects of ether and hypoxia are distinct. For example, ether promotes c-fos induction in the amygdala and lateral septum, whereas hypoxia does not (23, 24). Thus, the differential impact of vSUB lesion on hypoxia vs. ether may relate to lesion effects on specific circuits induced by the respective stimuli. The discrepancy between the current work and the previous hypoxia study may relate to differential involvement of vSUB-limbic circuitry responsible for generation of HPA axis responses. The previous study used fimbria-fornix cuts (18) rather than cell body lesions. Sectioning of the fornix does not affect vSUB efferents traveling in the ventral amygdalofugal path (25, 26), and thus it is possible that information traveling by way of the latter pathway may have significant impact on HPA responses to this stimulus. In addition, the Bradbury study also used adrenalectomized-replaced rats, which may hide effects of lesions on other aspects of HPA function, such as neuronally mediated pathways controlling adrenal sensitivity to ACTH (27).

As noted previously (10, 12), vSUB lesions do not affect resting CORT or ACTH levels, thymus weight, or adrenal weight. These observations reiterate a critical role for the vSUB in setting the magnitude and duration of the HPA response to stress rather than modulating basal or circadian secretory activity. In the hypoxia experiment, lesions primarily affect peak CORT secretion, whereas effects on EPM responses suggest (relatively minor) actions on response duration. These data suggest that the lesions affect different aspects of central stress integration. The attenuation of the hypoxia response is consistent with reduced peak CORT secretion, accomplished by enhanced inhibitory tone at the PVN and/or reduced activation of PVN excitatory afferents. On the other hand, the slight prolongation of responses to the EPM suggests that lesions may affect long-latency inhibition of PVN neurons.

The magnitude of the vSUB lesion effect on the CORT response to the EPM is smaller than that observed after other stimuli, such as restraint or open field (10, 12). The overall increase in CORT secretion after EPM is relatively circumspect and is limited to the recovery phase of the response. However, it is important to note that the elevation seen at the 120-min time point is unlikely to reflect a return to an elevated baseline level of secretion, because 1) resting CORT levels evaluated are not elevated in this cohort of animals when assayed later in time and 2) previous studies report that animals with vSUB lesions show normal basal morning and evening glucocorticoid secretion (10, 12). Thus, the differential increase in HPA activity seen after EPM is likely due to the relative salience of the psychogenic stressor and/or the degree of involvement of the hippocampus in processing the relevant stressful stimuli.

Animals with vSUB lesions showed reduced anxiety-related behavior in the EPM, manifest as increased time in the open arms of the maze. These data agree with a recent report showing similar reductions in fear-related behaviors in animals with ventral or total hippocampal lesions (28). Together, these studies indicate that ventral hippocampal lesions attenuate anxiety responses. These data are somewhat at odds with a previous study from our group, showing that vSUB-lesion animals show reduced ambulation upon open field exposure. These behavioral differences may be related to the different characteristics of the testing situations; for example, the contrast between areas of relatively low and relatively high risk may be more salient in the EPM. The divergent behavioral and endocrine data seen in the open field vs. EPM may also indicate that the underlying biological processes assayed by the two tests differ more than generally assumed.

It is important to note that the behavioral and HPA responses to the EPM are somewhat discordant; vSUB lesions reduce anxiety-related behavior but if anything slightly increase neuroendocrine responsiveness. The enhancement of CORT secretion after EPM testing may be linked to the anticipated risk associated with the behavior; by spending more time in the open arms, the vSUB lesion rats have a greater net exposure to the potential danger associated with the EPM. Alternatively, the increase in CORT seen at the 120-min time point in vSUB animals could reflect enhanced sensitivity to repeated blood sampling in this group, as previous studies suggest that hippocampal damage may increase sensitivity to mild stressors (9).

To enhance the power of the stressor comparison, neuroendocrine responses to hypoxia and EPM were sequentially assessed in the same animals. As a consequence, it is possible that responses to the EPM were affected by previous stress. However, we consider this possibility unlikely, as previous work shows that ventral hippocampal lesions also enhance open arm time in stress-naive animals (28).

In combination with previous findings (12, 29), the observation that the vSUB is involved in both excitation as well as inhibition of the HPA axis is at odds with the notion that limbic sites, such as the hippocampus, are involved only in mediating the effects of psychogenic stressors, defined as stimuli that do not directly represent an overt homeostatic challenge (21). Although vSUB inhibition of psychogenic activation of the PVN is upheld by these data, involvement in stress excitation by a direct systemic challenge (hypoxia) is a novel finding. The stressor-specific effects of vSUB lesion can be subserved by any of several possible mechanisms. First, stimulus dependence may be due to a differential impact of vSUB lesions on selected HPA-regulatory regions. Previous data from our group indicate that acute stress is accompanied by up-regulation of glutamic acid decarboxylase (GAD) 67 mRNA in select PVN-projecting nuclei that are afferent targets of the vSUB (26, 30). Elevated GAD expression implies increased biosynthesis of -aminobutyric acid (GABA); as such, modulation of GABA tone in vSUB-PVN relays may fundamentally alter response characteristics of PVN neurons to categorically diverse stimuli.

Second, the effects of the vSUB on the HPA axis may be related to stressor intensity. Although there are no direct data demonstrating the impact of stressor intensity on hippocampus-HPA interactions, it is important to note that 30-min hypoxia produced a substantially greater CORT response than 5-min EPM exposure in this study and as such may have a differential effect on hippocampal responsivity. Notably, previous studies provide some support for selective inhibitory effects of hippocampal lesions on mild stressors. For example, hippocampal lesions enhance CORT responses to the mild stress of cage relocation but not foot shock (9), and our previous work indicates that vSUB lesions enhance HPA responses to open field exposure but not to a more intense multimodal stimulus (ether inhalation) (10).

Finally, the results may reflect an ability of hippocampal outflow to both activate and inhibit HPA responses, depending on the nature or modality of the stressor. The circuitry that would underlie such stressor specificity is currently unclear. However, there is evidence for a direct, albeit minor, projection from the subiculum to brainstem regions, including the periaqueductal gray and medulla (25). The latter region contains populations of neurons that promote HPA activation, presenting an opportunity for long-loop relays to modulate hippocampal excitation of the PVN (21, 31). In addition, vSUB efferents also contact limbic regions implicated in HPA axis excitation, including the medial amygdaloid nucleus (32), and are in position to interact with PVN-projecting circuits in the hypothalamus (26, 33).

In summary, the current report documents a novel role for the hippocampus in HPA axis stress excitation as well as inhibition, depending on the modality and/or intensity of the stressor in question. The data argue against the hypothesis that the hippocampus is selectively involved in psychogenic stress integration, as posited previously by our group (21). Rather, regulation of the HPA system is likely mediated by an active integration across a diverse neuronal circuitry that assigns relative weights to various externally and internally perceived stimuli. Accordingly, removal of an individual component of this circuitry, such as the vSUB, can differentially affect HPA responsiveness to both stress-excitatory and stress-inhibitory inputs.

	Acknowledgments

 
We thank Megan E. Paskitti and the late Brian L. Bodie for their technical assistance on this project.

	Footnotes

 
This work was supported by Grants from the National Institute of Mental Health MH65770 (N.K.M.) and MH49698 (J.P.H.).

Abbreviations: CORT, Corticosterone; EPM, elevated plus maze; HPA, hypothalamic-pituitary-adrenal; PVN, paraventricular nucleus; vSUB, ventral subiculum.

Received January 27, 2004.

Accepted for publication May 4, 2004.

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